[6R-[6α,7β(Z)]]-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or (6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, generically known as ceftriaxone of formula (I) is a third generation cephalosporin antibiotic for parenteral administration.

It is commercially sold as the disodium hemiheptahydrate salt of formula (II), commonly referred to as ceftriaxone sodium, under the brand names Rocefin® and Rocephin(e)®.

Ceftriaxone sodium is the largest-selling intravenous (iv) cephalosporin antibiotic worldwide and has been safely prescribed for over 15 years in both adults and children. This broad spectrum antibiotic exhibits remarkable activity against Gram-positive and Gram-negative bacteria, organisms responsible for the majority of community-based infections. These include upper and lower respiratory tract infections, including otitis media, sinusitis, bronchitis and community-acquired pneumonia as well as soft tissue infections. These infections result in nearly 80 million treated patients in the United States alone. Ceftriaxone is primarily used to treat hospital in-patients.
Because of its therapeutic and commercial importance, there is always a demand for a process for manufacture of ceftriaxone sodium on industrial scale, which gives the product not only in high yield but also of superior quality and stability, thereby rendering it highly amenable for formulation into a suitable dosage form.
Ceftriaxone of formula (I) has generally been synthesised by two methods as described in the art. Both the methods involve amidification of the 7-amino function of 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid derivative of formula (A) either directly with (Z)-2-(2-amino thiazol-4-yl)-2-methoxyimino acetic acid or its reactive derivatives thereof of formula (B) [Method-I] or with a (Z)-4-halo-2-methoxyimino-butyric acid derivative of formula (C) to give a 7-substituted cephalosporin addendum of formula (D), which on reaction with thiourea forms the (Z)-2-(2-amino thiazol-4-yl)-2-oxyimino acetamido side chain and thereby, provide ceftriaxone of formula (I), after necessary deprotections, if any of protective groups [Method-II]. The ceftriaxone (I) thus obtained is converted to the sodium salt of formula (II) by methods known in the art. The two methods of synthesis are summarized in Scheme-I.
In compounds of formula (A), (B), (C) and (D) of Method-I and II, the meanings of the groups R, R1 and X are as defined therein and the groups Y and Z represent hydrogen or a group which forms a basis that compound of formula (B) and (C) are in a reactive form.
As per Method-I, synthesis of ceftriaxone (I) has been achieved by several ways, all differing in the choice of the reactive group Y. The following prior art methods illustrate the synthesis of ceftriaxone utilizing different reactive species as embodied in the group Y. These are, to name a few achieved through:                (i) Activation of the carboxylic acid (B, wherein Y═H) as the acid halide, as disclosed in Japanese Patent Nos. JP 52-102096, JP 53-157596 and British Patent No. GB 2,025,933. The acid halide, in particular the acid chloride is prepared by reaction of the 2-(2-amino thiazol-4-yl)-2-oxyimino acetic acid with PCl3, PCl5, SOCl2 or POCl3.        (ii) Activation of the carboxylic acid (B, wherein Y═H), through formation of its mixed anhydride, an active amide or an active ester, as disclosed in EP Patent No. 0,045,525.        (iii) Activation of the carboxylic acid (B, wherein Y═H), through formation of the activated ester by reaction of the carboxylic acid group with an acyloxyphosphonium chloride derivative, as disclosed in U.S. Pat. No. 5,317,099. The method of preparation comprises reacting the corresponding carboxylic acid derivative with triphenyl phosphine, hexachloroethane or carbon tetrachloride. However, this method increases the overall cost of the coupling reaction since it involves the use of expensive triphenyl phosphine.        
                (iv) Activation of the carboxylic acid (B, wherein Y═H), through formation of the activated benzothiazolyl thioester, in turn prepared by reaction of the carboxylic acid compound with bis[benzothiazolyl-(2)]disulfide and triphenyl phosphine, as disclosed in EP Patent Nos. EP 0 037 380. This method, however, utilizes expensive triphenyl phosphine for preparation of the activated ester.        (v) Activation of the carboxylic acid (B, wherein Y═H), by derivatisation with dimethyl formiminium chloride chlorosulfite (DFCS), as disclosed in U.S. Pat. No. 5,037,988. The dimethyl formiminium chloride chlorosulfite (DFCS) is in turn prepared by reacting equimolar quantities of thionyl chloride and N,N-dimethylformamide at room temperature. The method however, suffers from a drawback in that the amide forming reaction, utilizing the said activated reactive derivative can be effected in only specific solvents like benzene and toluene.        (vi) Activation of the carboxylic acid (B, wherein Y═H), by derivatisation with N,N dimethyl formiminium chloride chlorosulphate (DFCCS), as disclosed in U.S. Pat. No. 5,739,346. The N,N dimethyl formiminium chloride chlorosulphate (DFCCS) is in turn prepared by reacting equimolar quantities of sulfuryl chloride and N,N dimethylformamide at room temperature.        (vii) Activation of the carboxylic acid (B, wherein Y═H), as the thiophosphoryl ester, as disclosed in U.S. Pat. No. 5,567,813.        (viii) Activation of the carboxylic acid (B, wherein Y═H), as a 2-mercapto-5-substituted-1,3,4-oxadiazole derivative as disclosed in U.S. Pat. No. 6,388,070.        
Synthesis of ceftriaxone (I) as per Method-I1 is equally widely documented in the literature. Several methods, varying subtly in the choice of the reactive group Z of compounds of formula (C) have been utilised, albeit the choice of the activating group is primarily restricted to acid halides. A few such methods are:                (a) U.S. Pat. No. 5,109,131 describes a process for preparation of 7-[2-(2-amino thiazol-4-yl)-oxyimino acetamido cephalosporin compounds, carrying a “residue of a nucleophile” in the 3α-position, which includes inter alia ceftriaxone. The method utilizes tert-butyl-3-oxobutyrate as an intermediate, which is reacted as such or a reactive derivative thereof is reacted with compound of formula (A) to form the 7-substituted cephalosporin addendum (D), which on reaction with thiourea gives ceftriaxone. The reactive derivatives utilised for 7-amidification as disclosed in U.S. Pat. No. 5,109,131 include acid halides, a mixed acid anhydride, an active amide or an active ester. The chemistry is summarized as shown hereinbelow in Scheme-I1        (b) European Patent No. 0,030,294 (and its equivalent in Canada, CA 1 146 165) claims ceftriaxone and its esters and a process for preparation thereof comprising the following steps as described in Example-1 of said patent i.e.                    b.1 reacting (7R)-Amino-3-desacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid (corresponding to Compound A of Scheme-I) with N,O-bis-(trimethylsilyl)-acetamide in ethyl acetate at 25° C. for 30 minutes to form the corresponding (N,O)-bis-silyl derivative;            b.2 addition of a solution of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride (Corresponding to Compound C of Scheme-I) in dichloromethane to the solution of the (N,O)-bis-silyl derivative in ethyl acetate thus obtained in step b.1 and after work up, crystallization of the residue from etherpetroleum ether to give (6R,7R)-7-[[4-Bromo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid [corresponding to compound (D) of Scheme-I];                        
                                    b.3 reaction of the (6R,7R)-7-[[4-Bromo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid obtained above with thiourea in absolute alcohol to give the hydrobromide salt of ceftriaxone; and            b.4 neutralisation of ceftriaxone hydrobromide salt with sodium methoxide in a mixture of water and acetone to give ceftriaxone (I), which is isolated by filtration.                        
The chemistry disclosed in EP Patent No. 0,030,294 is summarized in Scheme-III.                (c) European Patent No. 0,842,937 claims a process for preparation of ceftriaxone and cefotaxime comprising reaction of 7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic acid (compound III of Scheme-I) and 7-ACA respectively with 4-chloro-2-methoxyimino-3-oxobutyric acid, activated as 2-mercaptobenzothiazolyl ester, followed by cyclization of the intermediate thus obtained with thiourea to give ceftriaxone and cefotaxime respectively. The chemistry disclosed in EP Patent No. 0,842,937 is summarized in Scheme-IV.        

                (d) The process disclosed in EP Patent No. 0,556,768 essentially is an improvement over the one described in EP Patent No. 0,842,937, wherein the method for preparation of ceftriaxone comprises reaction of 7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic acid (compound A of Scheme-I) with 4-chloro-2-methoxyimino-3-oxobutyric acid, activated as 2-mercaptobenzothiazolyl ester, followed by cyclization of the intermediate thus obtained with thiourea to give ceftriaxone. The improvement this patent claims is that the abovementioned reaction and subsequent conversion of ceftriaxone to its disodium hemiheptahydrate salt can be carried out in one pot using a mixture of acetone and water as solvent.        (e) U.S. Pat. No. 6,384,215 provides yet another variation, wherein the compound V of Scheme-I is activated as a 2-mercapto-5-substituted-1,3,4-oxadiazole derivative prior to 7-amidification, followed by cyclization of the intermediate compound thus obtained with thiourea to give ceftriaxone,        (f) The recently issued U.S. Pat. No. 6,552,186 B2 claims a method for preparation of ceftriaxone comprising reaction of (N,O)-bis silylated 7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic acid (compound A of Scheme-I) with 4-halo-2-methoxyimino-3-oxobutyric acid, suitably activated as a reactive derivative (compound C of Scheme-I) to give the corresponding intermediate 7-acylated compound (D of Scheme-I, wherein the group R1 attached to the carboxylic acid function at the 4-position is a trialkyl silyl group), followed by either,                    (i) reaction of the 7-acylated compound (D of Scheme-I, wherein the group R1 attached to the carboxylic acid function at the 4-position is a trialkyl silyl group), with silylated thiourea to form the aminothiazole ring, which after necessary desilylation gives ceftriaxone, (as claimed in claim 3a of said patent); or            (ii) desilylation of the 7-acylated compound (D of Scheme-I, wherein the group R1 attached to the carboxylic acid function at the 4-position is a trialkyl silyl group), followed by reaction of the desilylated compound thus obtained with thiourea to give ceftriaxone (as claimed in claim 3a of said patent).            In addition, the U.S. Pat. No. 6,552,186 B2, claims the 7-acylated compound (D of Scheme-I, wherein the group R1 attached to the carboxylic acid function at the 4-position is a trialkyl silyl group) as represented in Chart-I hereinbelow as a novel compound.                        
                                    The U.S. Pat. No. 6,552,186 B2 further claims that the reaction of the desilylated compound with thiourea is effected in the presence of a solvent system containing an organic solvent and water to give ceftriaxone. The chemistry claimed in claims 3a and 3a1 of the U.S. Pat. No. 6,552,186B2 for synthesis of ceftriaxone is summarized in Scheme-V. However, the chemistry embodied in claim 3a1 of the U.S. Pat. No. 6,552,186 B2 not only lacks novelty but is anticipated from the prior art methods discussed hereinbefore as well as those summarized hereinbelow, as would be apparent to a person skilled in the art from the discussion contained hereinbelow:                            f.1 The invention apparently residing in U.S. Pat. No. 6,552,186 B2 is use of a silylated compound i.e. (6R,7R)-7-[[4-Bromo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid, wherein the carboxylic acid function is silylated for subsequent reaction with,                                    (a) silylated thiourea to give ceftriaxone after desilylation (as claimed in Claim 3a of said patent); or            (b) desilylation of the silyl compound and reaction of the desilylated compound thus obtained with thiourea to give ceftriaxone (as claimed in Claim 3a1 of said patent).                        
                                                                f.2 However, the said chemistry is identical and superimposable to that disclosed in Example-1 of EP Patent No. 0,030,294, summarized in Scheme-III, which, needless to mention has an early priority of nearly twenty years than the priority date of U.S. Pat. No. 6,552,186 B2.                The only difference in both the processes is in the choice of solvents, reaction temperatures and mode of isolation of the product. However, both the methods function the same way giving substantially the same result, thereby indicating that the change in parameters and solvents are inconsequential and have no bearing in the course of the reaction,                f.3 Moreover, the compound claimed in claim 1 of U.S. Pat. No. 6,552,186 B2 (as summarized in Chart-I) lacks novelty since the same compound is obtained and reported, albeit not specified in the process embodied in Example-1 of EP Patent No. 0,030,294.                f.4 Further, that portion of claim 3a1 of U.S. Pat. No. 6,552,186 B2 claiming that the reaction of the desilylated compound with thiourea is effected in the presence of a solvent system containing an organic solvent and water to give ceftriaxone also is anticipated from the teachings of U.S. Pat. No. 5,109,131, wherein a mixture of organic solvent and water i.e. mixture of tetrahydrofuran and water has been specified and used for cyclization of a structurally similar compound with thiourea for formation of the aminothiazolyl addendum at the 7-amino position, as evident from WORKING EXAMPLE; 3 (4), column 13 of said patent,                f.5 With regard to protection of the carboxylic acid function at 4-position of a cephalosporonic acid derivative as a trialkylsilyl group prior to amidification at 7-position as claimed in Claim 3a1 of U.S. Pat. No. 6,552,186 B2 it can be termed at the most “trivial” and not substantially contributing to the development of cephalosporin chemistry in any way. Similarly, deprotection of the said “trialkylsilyl” protective group is also “trivial” and has no substantial bearing in the course of the reaction.                There is a wealth of literature, wherein the carboxylic acid function at 4-position and/or the amino function at 7-position of a cephalosporin derivative have been protected through silylated derivatives prior to amidification. From these, it would be abundantly evident that claims for protection and deprotection through silylation residing in U.S. Pat. No. 6,552,186 B2 is not novel and is anticipated and obvious to a person skilled in the art. Protection of reactive functional groups, specially the carboxylic acid function at 4-position and the amino function at 7-position through silylation is widely practiced in cephalosporin chemistry since many years. As early as 1964 acylation of 6-aminopenicillinate esters (6-APA) to give commercially valuable antibiotics such as ampicillin and amoxycillin have been achieved through protection of the carboxylic acid function at 3-position as trialkyl silyl esters [Glombitza, K. W., Ann, 1964, 166].                This publication teaches acylation of 6-aminopenicillinate (6-APA) esters having an easily removable carboxyl protecting group and, therefore, soluble in organic solvents. The author discovered that 6-APA trialkyl silyl esters could be readily obtained by reacting 6-APA with hexamethyldisilazane in chloroform and the ester thus obtained could be successfully acylated with acid chlorides or by the mixed anhydride method. The advantage cited is that the silyl group could be removed merely by treatment with water during the workup procedure. Several penicillins were synthesized in high yields (65-98%) by this method, which is summarized in Scheme-VI.                                                
                                                                Similarly, an improved method for preparation of 7-acylamidocephalosporanic acids by acylation of the 7-ACA esters was reported as early as 1963, wherein the inventors have claimed that best results were achieved by silyl esters of 7-ACA since the ester group was easily removed by mild acidic work-up (Jackson et. al., GB Patent No. 1,073,530).                This patent teaches an improved procedure for the preparation of 7-acylamidocephalosporanic acids by acylating the 7-ACA esters which are soluble in organic solvents. The patent claims that best results were achieved by using the silyl esters of 7-ACA since the ester group was easily removed by mildly acidic conditions during the workup procedure.                The chemistry is summarized in Scheme-VII.                                                
                (g) In addition, replication of the prior art methods, specially the process embodied in Example-2 of U.S. Pat. No. 6,552,186 B2 for preparation of ceftriaxone sodium is found to be associated with the following shortcomings in that:                    g.1 the reaction (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid with 4-halo-2-methoxyimino-3-oxo-butyric acid halide to give (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid trialkylsilyl ester, does not proceed to completion and about 10% of starting compound i.e (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid remains unreacted,            g.2 precipitation of ceftriaxone occuring during reaction of (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid (after subsequent hydrolysis of the trialkylsilyl carboxylic ester) with thiourea, which not only because of the incompletion of reaction in the precursor step but also because of formation of higher level of impurities in the reaction result in production of ceftriaxone in lower yield, and of unsatisfactory quality and            g.3 conversion of ceftriaxone thus produced to ceftriaxone sodium is found to give a colored product i.e. very high color absorbance of 1.0 to 1.8 AU at 450 nm, having a purity of about 73-80%, and containing higher level of impurities,                        all contributing to and resulting in production of ceftriaxone and ceftriaxone sodium of quality and nature not conforming to pharmacopoeial specifications and therefore, rendering the product not only unsuitable for formulation into a dosage form but also for administration to human beings.        
Further, replication of the methods described in other prior art methods, mentioned hereinbefore also were found to afford the product in unsatisfactory yields and quality, rendering them less cost-effective.
Thus, from the foregoing it would be apparent that there is a need for a method for manufacture of ceftriaxone (I) and ceftriaxone sodium (II), not only in a cost-effective manner but with vastly improved stability, high purity, and excellent physical characteristics, such as flowability and color absorbance.
It is therefore, an object of the present invention to provide a cost-effective method for manufacture of ceftriaxone sodium in high yield, possessing high purity, improved stability, low color absorbance, hitherto not been achieved in prior art.
The present inventors have found that such an objective could be achieved through a selection of the right quality of reactants, type of solvents, pH, other reaction conditions or parameters etc., which are surprising findings, thus forming the inventive step of the present invention.
In particular, the present inventors have found that the level of impurities in the finished product i.e. ceftriaxone sodium, in turn arising out of their formation at various stages of the process could be minimized, the efficiency of the reaction at each stage of the chemical sequence could be enhanced and the color absorbance of the finished product could be drastically improved and ceftriaxone of formula (I) could be obtained in high purity in one pot and converted to ceftriaxone sodium of formula (II), possessing the desired object characteristics, through a selection of the night quality of reactants, type of solvents, pH, other reaction conditions or parameters etc., when:                (a) a 4-halo-2-methoxyimino-3-oxo-butyric acid halide derivative having a purity of at least 95%, preferably of about 97-98%, containing less than 0.50% of di-and polybrominated compounds and preferably prepared and purified as per the method disclosed in our published PCT Application No. WO 03/045899 A1, is utilized for reaction with (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid in the presence of a inert water-immiscible organic solvent to give (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid trialkylsilyl ester;        (b) the aforementioned reaction of 4-halo-2-methoxyimino-3-oxo-butyric acid halide derivative having the said purity with (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid in the presence of a inert water-immiscible organic solvent to give (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid trialkylsilyl ester is carried out in the presence an acid scavenging agent;        (c) in the hydrolysis of the trialkyl ester group of (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid trialkylsilyl ester to give the corresponding (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid, the said hydrolysis of the trialkylsilyl ester is effected, without its isolation from the reaction mixture with approximately a 1:1 mixture of water and a water-miscible organic solvent selected from tetrahydrofuran and acetonitrile, wherein the hydrolysed compound is portioned in the inert water-immiscible organic solvent phase;        
(d) in the step of reaction of the solution of (6R,7R)-7-[[4-halo-2-(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-3-cephem-4-carboxylic acid in the inert water-immiscible organic solvent with thiourea, the said reaction is carried out in presence of water, the precipitation of ceftriaxone along with impurities is avoided by carrying out the reaction in the presence of an inorganic base selected from alkali metal containing inorganic bases, rather than an organic base and at a pH of between 5.0 to 5.5, which leads to formation of the alkali metal salt of ceftriaxone, wherein the said alkali metal salt of ceftriaxone thus formed is completely partitioned in the aqueous phase, and wherein it remains as a solution and does not separate out, while the associated impurities are selectively partitioned in the inert water-immiscible organic solvent phase. Neutralization of the alkali metal salt gives ceftriaxone in higher yield and substantially free of impurities, which is isolated; and                (e) in the step of formation of ceftriaxone sodium, the ceftriaxone thus obtained is first converted to an amine salt by reaction with an organic amine, maintaining strictly a pH of 5.4±0.2 and reacting the amine salt thus formed without isolation with a sodium metal carrier to give ceftriaxone sodium in high yield, possessing high purity, containing impurities in the range of 0.05 to 0.20% and possessing low color absorbance in the range of 0.04-0.05 AU.        
The effect of using a 4-halo-2-methoxyimino-3-oxo-butyric acid halide derivative having a purity of at least 95%, preferably having a purity of 97-98% and utilization of an acid scavenging agent in tandem in the reaction ensures not only completion of reaction but also in effective neutralization of hydrogen halide formed during the reaction, thereby contributing to the desired objective.
Similarly, the utilization of the right pH, the choice of the alkali metal inorganic base, the selection of the right water-miscible organic solvent in the subsequent steps also contributes in achieving the desired objective, overall providing a vastly improved method cost-effective method for manufacture of ceftriaxone of formula (I) and ceftriaxone sodium of formula (II).